Clonogenic assays measure the ability of single cells to proliferate and form a colony. This process approximates closely the regrowth and recurrence of tumors after treatment with radiation or chemotherapy, providing an assay to screen for drugs that block this process. Yet, clonogenic assays are labor-intensive and too cumbersome for high throughout screening (HTS) of compound libraries. Here we propose to develop an HTS system based on a clonogenic endpoint. This proposal is based on a completed Phase I contract wherein we successfully generated Head and Neck Cancer cells amenable to miniaturization into multi-well format with automated colony counting. Proof of concept tests using known radiation modulators demonstrate that this system faithfully represents the traditional clonogenic assays. In the Phase II contract, we will screen through compound libraries, generate additional cell lines to represent other cancer types, and develop a fully integrated automated system that plates cells, irradiates, exposes them to drug, and counts colonies. This system will be transferrable to other laboratories. Potential commercial applications include screening libraries for new compounds with the potential to inhibit regrowth of tumors after treatment and to rapidly identify efficacious pair-wise combinations among existing oncology agents.